Atiya Mansoor

Phase I Trial of Preoperative Chemoradiation Plus Sorafenib for High Risk Extremity Soft Tissue Sarcomas with Dynamic Contrast-Enhanced MRI Correlates

Purpose: We conducted a phase I trial of the addition of sorafenib to a chemoradiotherapy regimen in patients with high-risk (intermediate/high grade, >5 cm) extremity soft tissue sarcoma undergoing limb salvage surgery. We conducted a correlative study of quantitative dynamic contrast-enhanced MRI (DCE-MRI) to assess response to treatment. Experimental Design: Patients were treated at increasing dose levels of sorafenib (200 mg daily, 400 mg daily, 400 mg twice daily) initiated 14 days before three preoperative and three postoperative cycles of epirubicin/ifosfamide. Radiation (28 Gy) was administered during cycle 2 with epirubicin omitted. The primary objective was to determine the maximum tolerated dose (MTD) of sorafenib. DCE-MRI was conducted at baseline, after 2 weeks of sorafenib, and before surgery. The imaging data were subjected to quantitative pharmacokinetic analyses. Results: Eighteen subjects were enrolled, of which 16 were evaluable. The MTD of sorafenib was 400 mg daily. Common grade 3–4 adverse events included neutropenia (94%), hypophosphatemia (75%), anemia (69%), thrombocytopenia (50%), and neutropenic fever/infection (50%). Of note, 38% developed wound complications requiring surgical intervention. The rate of ≥95% histopathologic tumor necrosis was 44%. Changes in DCE-MRI biomarker ΔKtrans after 2 weeks of sorafenib correlated with histologic response (R2 = 0.67, P = 0.012) at surgery. Conclusion: The addition of sorafenib to preoperative chemoradiotherapy is feasible and warrants further investigation in a larger trial. DCE-MRI detected changes in tumor perfusion after 2 weeks of sorafenib and may be a minimally invasive tool for rapid assessment of drug effect in soft tissue sarcoma. Clin Cancer Res; 19(24); 6902–11. ©2013 AACR.

Lineage of origin in rhabdomyosarcoma informs pharmacological response

Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3:Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3:Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3:Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3:Foxo1.

Histologic response of dose-intense chemotherapy with preoperative hypofractionated radiotherapy for patients with high-risk soft tissue sarcomas

The authors studied a dose‐intense regimen of epirubicin and ifosfamide with hypofractionated preoperative radiotherapy for high‐risk soft tissue sarcomas. The primary objective was estimation of the rate of ≥95% pathologic necrosis.

Cytogenetic analysis of a hemosiderotic fibrolipomatous tumor

Hemosiderotic fibrolipomatous tumor is an extremely rare, nonencapsulated, fatty lesion with a consistent histologic appearance that was originally considered reactive in nature. To our knowledge, there are no previous reports on the cytogenetics of this lesion. Reported here is a case of hemosiderotic fibrolipomatous tumor arising within the subcutaneous tissue of the right foot, dorsal aspect, of an otherwise healthy 35-year-old woman. Subsequent cytogenetic analysis revealed a clonal reciprocal translocation between chromosomes 1 and 10, with a further rearrangement involving this derivative chromosome 1 and chromosome 3. This, in addition to its characteristic morphology and immunophenotype, supports the neoplastic nature of this tumor and may aid in its diagnosis.

Cytogenetic analysis of a primary bone angiosarcoma

Primary bone angiosarcomas are rare and aggressive vascular malignancies with a high mortality rate. To our knowledge, there are no reported cytogenetic abnormalities in primary bone angiosarcomas, although several have been reported in soft tissue angiosarcomas. We report a case of primary bone angiosarcoma, arising in the tibia of a 79-year-old woman, with a unique clonal chromosomal rearrangement: t(1;14)(p21;q24), that has not been reported in either soft tissue or primary bone angiosarcoma. The biologic significance of this translocation is not clear; however, the 1p21 locus is in the region of colony stimulating factor (CSF-1), which may play a role in tumorigenesis, as has been described in pigmented villonodular synovitis and tenosynovial giant cell tumor.

Orbital and periorbital myofibromas in childhood ☆: Two case reports

PURPOSE Infantile myofibromatosis is an uncommon tumor that occurs rarely in the periorbit and orbit. This article reports two cases of infantile myofibromatosis of the orbital adnexa and describes the associated clinical, histopathologic, and immunohistochemical findings. DESIGN Two retrospective, interventional case reports with clinicopathologic correlation. INTERVENTION Treatment consisted of excision of the tumors. MAIN OUTCOME MEASURES Histologic and immunohistochemical evaluation and clinical evaluation for tumor recurrence. RESULTS The first patient was a newborn male with a large tumor extending from his eyelid that was excised at day 2 of life. Histologic and immunohistochemistry analyses were used to make a diagnosis of infantile myofibromatosis. He remains disease free at age 7 years. The second case was a 6-year-old boy with a 1-month history of proptosis resulting from an orbital mass. Incisional biopsy revealed a tumor consistent with infantile myofibromatosis. He remains tumor free 12 months after complete gross surgical resection. CONCLUSIONS Infantile myofibromatosis is an uncommon tumor that is rare in the orbit. Differential diagnosis can be difficult based solely on histologic analysis. Immunohistochemistry evaluation demonstrating cytoplasmic actin filaments within neoplastic spindle cells confirms the diagnosis. As soon as the diagnosis is made, chest and abdominal imaging is of value to define the prognosis and to direct further treatment. After the diagnosis of nonvisceral infantile myofibromatosis, complete gross resection, if possible, is the treatment of choice.

A case study of personalized therapy for osteosarcoma.

Effective targeted therapies are needed in sarcomas, but the biological heterogeneity of these tumors has presented a challenge to clinical integration of small molecule inhibitors in sarcoma treatment. Here we outline a process to personalize therapy for sarcomas through a case study of a canine with spontaneous osteosarcoma.

Dynamic and Nuclear Expression of PDGFRα and IGF-1R in Alveolar Rhabdomyosarcoma

Since the advent of tyrosine kinase inhibitors as targeted therapies in cancer, several receptor tyrosine kinases (RTK) have been identified as operationally important for disease progression. Rhabdomyosarcoma (RMS) is a malignancy in need of new treatment options; therefore, better understanding of the heterogeneity of RTKs would advance this goal. Here, alveolar RMS (aRMS) tumor cells derived from a transgenic mouse model expressing two such RTKs, platelet-derived growth factor (PDGFR)α and insulin-like growth factor (IGF)-1R, were investigated by fluorescence-activated cell sorting (FACS). Sorted subpopulations that were positive or negative for PDGFRα and IGF-1R dynamically altered their cell surface RTK expression profiles as early as the first cell division. Interestingly, a difference in total PDGFRα expression and nuclear IGF-1R expression was conserved in populations. Nuclear IGF-1R expression was greater than cytoplasmic IGF-1R in cells with initially high cell surface IGF-1R, and cells with high nuclear IGF-1R established tumors more efficiently in vivo. RNA interference–mediated silencing of IGF-1R in the subpopulation of cells initially harboring higher cell surface and total IGF-1R resulted in significantly reduced anchorage-independent colony formation as compared with cells with initially lower cell surface and total IGF-1R expression. Finally, in accordance with the findings observed in murine aRMS, human aRMS also had robust expression of nuclear IGF-1R. Implications: RTK expression status and subcellular localization dynamics are important considerations for personalized medicine. Mol Cancer Res; 11(11); 1303–13. ©2013 AACR.

Pulmonary Artery Sarcoma Mimicking Massive Pulmonary Embolus: A Case Report

Intimal sarcomas of the pulmonary artery are rare tumors that are often difficult to distinguish from pulmonary thromboembolic disease, complicating accurate diagnosis and timely therapy. We report the case of a gentleman with a primary pulmonary artery sarcoma who presented with a massive pulmonary embolism and complete right ventricular outflow tract obstruction. The patients condition was successfully managed with urgent pulmonary artery thromboendarterectomy, pulmonary valve replacement, and tricuspid valve annuloplasty.

PDGFRβ reverses EphB4 signaling in alveolar rhabdomyosarcoma

Significance Effective targeted therapies to complement already intensive chemotherapy are much needed for the childhood muscle cancer rhabdomyosarcoma, yet few targeted agents have been identified that improve long-term survival. In particular, the alveolar subtype of rhabdomyosarcoma accounts for disproportionate mortality. Herein, the receptor tyrosine kinase EphB4 is identified as a potential two-way switch for alveolar rhabdomyosarcoma. Whereas the typical EphB4 ligand, EphrinB2, drives tumor cells toward apoptosis, the interaction between EphB4 and another receptor tyrosine kinase, PDGFRβ, drives tumors to proliferate in the presence of the PDGFRβ ligand, PDGF-BB. The Food and Drug Administration-approved dual EphB4-PDGFRβ inhibitor, dasatinib, is found to have significant preclinical activity, which is clinically relevant because EphB4 and PDGFRβ are independent poor prognostic factors in this childhood disease. Alveolar rhabdomyosarcoma (aRMS) is an aggressive myogenic childhood malignancy, not infrequently presenting as incurable metastatic disease. To identify therapeutic targets, we performed an unbiased tyrosine kinome RNA interference screen in primary cell cultures from a genetically engineered, conditional mouse model of aRMS. We identified ephrin receptor B4 (EphB4) as a target that is widely expressed in human aRMS and that portends a poor clinical outcome in an expression level-dependent manner. We also uncovered cross-talk of this ephrin receptor with another receptor tyrosine kinase, PDGFRβ, which facilitates PDGF ligand-dependent, ephrin ligand-independent activation of EphB4 converging on the Akt and Erk1/2 pathways. Conversely, EphB4 activation by its cognate ligand, EphrinB2, did not stimulate PDGFRβ; instead, apoptosis was paradoxically induced. Finally, we showed that small-molecule inhibition of both PDGFRβ and EphB4 by dasatinib resulted in a significant decrease in tumor cell viability in vitro, as well as decreased tumor growth rate and significantly prolonged survival in vivo. To our knowledge, these results are the first to identify EphB4 and its cross-talk with PDGFRβ as unexpected vital determinants of tumor cell survival in aRMS, with EphB4 at the crux of a bivalent signaling node that is either mitogenic or proapoptotic.